β-Acyloxy enamide derivatives and preparation methods and applications thereof

Abstract

The invention discloses β-acyloxy enamide derivatives and preparation methods and applications thereof, and relates to the field of organic synthetic chemistry. The preparation method of β-acyloxy enamide derivatives includes: mixing acyl chloride, aluminum chloride and solvent at 50°C to 70°C, adding vinylidene chloride to mix, and reacting to obtain α-trichloromethyl ketone; mixing α-trichloromethyl ketone with carboxylic acid or amino acid, secondary amine, solvent and catalyst, and reacting at 30°C to 50°C to obtain; the preparation method of amide and / or polypeptide includes: stirring and reacting β-acyloxy enamide derivatives with amine compounds and solvents under 0~80°C, using TLC spot plate monitoring until the reaction is completed, and obtaining a reaction solution; separation and purification to obtain. The beneficial effect of the present invention is that the preparation of α-trichloromethyl ketone does not require separation and purification, saves costs, and improves efficiency; the prepared β-acyloxy enamide belongs to activated carboxylic acid, which is conducive to the synthesis of amide and / or polypeptide.

Description

Technical Field

[0001] The present invention relates to the field of organic synthetic chemistry, and in particular to beta-acyloxy enamide derivatives and preparation methods and applications thereof. Background Art

[0002] Amide bonds are widely present in natural and artificially synthesized compounds. They are not only one of the most important chemical bonds in nature, but also one of the most basic chemical bonds in organic synthetic chemistry. It is generally believed that amide bonds can be obtained by dehydration condensation of two amino acids, but it is difficult to selectively obtain the target product through this method because polymerization will occur between amino acids of the same type. The solution to the "polymerization problem" is to protect the amino and carboxyl groups of amino acids separately, and then remove a molecule of water from the two to form the target amide bond in a directional manner. However, the reaction temperature is high, which can easily denature proteins and destroy the polypeptide structure, so this strategy is still not an ideal choice.

[0003] In order to avoid the use of high temperature in the process of forming amide bonds, the "activated ester method" came into being. This method uses a condensation reagent to convert amino acids into activated esters, and the activated esters and free amino groups undergo an aminolysis reaction to obtain amide bonds. The reaction can be carried out under mild conditions, but there are still some obvious problems. For example, some condensation agents are too active. If the α position of the reactant is chiral at this time, it is easy to cause the reactant to racemize; some condensation agents themselves are not stable enough, which can easily bring safety hazards to operators in scale-up production. In addition, there are problems such as low coupling efficiency, large amounts of waste after the reaction, and increased costs. Moreover, compared with small molecule drugs, the drugability of polypeptide drugs is better in clinical phase I, clinical phase II, and clinical phase III. Therefore, the development of green, environmentally friendly, mild, efficient, and not prone to racemization condensation reagents will contribute to the development of the field of polypeptide synthesis, which is urgently needed in the current field of polypeptide synthesis. Summary of the invention

[0004] The purpose of the present invention is to solve at least one of the technical problems existing in the prior art and to provide a β-acyloxy enamide derivative and a preparation method and application thereof. This type of compound is a typical activated carboxylic acid, which can be activated by reacting it with an amino acid for efficient synthesis of amides and peptides.

[0005] The technical solution of the present invention is as follows:

[0006] In a first aspect, the present invention provides a method for preparing a β-acyloxy enamide derivative, comprising the following steps:

[0007] S1, mixing acyl chloride, aluminum chloride and solvent at 50°C to 70°C, and adding vinylidene chloride to mix, and reacting to obtain α-trichloromethyl ketone;

[0008] S2, mixing the α-trichloromethyl ketone with carboxylic acid or amino acid, secondary amine, solvent and catalyst, and reacting at 30° C. to 50° C. to prepare a β-acyloxy enamide derivative.

[0009] Optionally, in S1, the molar ratio of the acyl chloride, aluminum chloride and vinylidene chloride is 1:0.5-1.5:1-3;

[0010] In S2, the molar ratio of the α-trichloromethyl ketone, carboxylic acid or amino acid, secondary amine and catalyst is 1:2~4:1~2:2~3.

[0011] Optionally, in S1, the mixing time of the acyl chloride, aluminum chloride and solvent is 20 min to 40 min, and the mixing time after the vinylidene chloride is continuously added is 40 to 80 min;

[0012] In S2, the reaction is carried out at 30°C-50°C and monitored by TLC until the reaction is completed.

[0013] Optionally, in S2, the carboxylic acid is one or more of fatty acid, aromatic acid, heterocyclic acid and olefinic acid; the secondary amine is one or more of diethylamine, diisobutylamine and di-n-propylamine; and the catalyst is cesium carbonate.

[0014] Optionally, in S2, the carboxylic acid or amino acid is one or more of benzoic acid, 4-methylbenzoic acid, m-fluorobenzoic acid, 2-iodo-5-methylbenzoic acid, cyclohexanecarboxylic acid, sorbic acid, veratric acid, ibuprofen, flurbiprofen, furoic acid, Boc-L-tryptophan, Fmoc-L-aspartic acid-beta-tert-butyl ester, thiophenecarboxylic acid, Boc-L-proline, pyrrole-2-carboxylic acid, 2-bromobenzoic acid, Boc-L-serine, 2,3,5-triiodobenzoic acid and Cbz-L-alanine.

[0015] In a second aspect, the present invention provides a β-acyloxyenamide derivative prepared by the above method.

[0016] In a third aspect, the present invention provides a method for preparing an amide and / or a polypeptide, using the above-mentioned β-acyloxy enamide derivative as a raw material, comprising the following steps:

[0017] The β-acyloxy enamide derivative, the amine compound and the solvent are continuously stirred and reacted at 0-80°C, and a TLC spot plate is used to monitor until the reaction is completed to obtain a reaction solution;

[0018] The reaction solution is separated and purified to obtain amide and / or polypeptide.

[0019] Optionally, the molar ratio of the β-acyloxy enamide derivative to the amine compound is 1-3:1-3, and the amine compound is a secondary amine.

[0020] Optionally, the amine compound is one or more of L-valine tert-butyl ester, L-aspartic acid tert-butyl ester, L-tyrosine tert-butyl ester, L-phenylalanine tert-butyl ester and O-tert-butyl-L-serine tert-butyl ester hydrochloride.

[0021] In a fourth aspect, the present invention provides an amide and / or polypeptide prepared by the above method.

[0022] The present invention has at least one of the following beneficial effects:

[0023] 1. The present invention discloses a simple and efficient method for preparing β-acyloxy enamide derivatives. Specifically, the steps for preparing β-acyloxy enamide derivatives in the present invention are divided into two steps. First, α-trichloromethyl ketone is prepared, and then the β-acyloxy enamide derivatives are directly prepared by reacting with secondary amines and carboxylic acids or amino acids without separation and purification. In this method, both carboxylic acids and N-protected amino acids show good compatibility, and secondary amines of different structures also have good compatibility with the reaction. This feature is of vital importance for the subsequent use of such compounds to synthesize peptides.

[0024] 2. The present invention also relates to the application of β-acyloxy enamide derivatives in the synthesis of amides and polypeptides. The amide bond construction reaction can be achieved at room temperature or a temperature close to that, thereby efficiently obtaining amide products. The obtained polypeptide products are all optically pure samples, and no racemization phenomenon occurs during the reaction. This fully confirms that the method of the present invention has great application prospects in the fields of amide synthesis and peptide condensation. DETAILED DESCRIPTION

[0025] In order to make the technical problems, technical solutions and beneficial effects solved by the present invention more clearly understood, the present invention is further described in detail below in conjunction with the embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0026] One embodiment of the present invention provides a mild and efficient method for preparing a β-acyloxy enamide derivative, comprising the following steps:

[0027] S1, mixing acyl chloride, aluminum chloride and solvent at 50°C to 70°C, and adding vinylidene chloride to mix, and reacting to obtain α-trichloromethyl ketone;

[0028] S2, mixing the α-trichloromethyl ketone with carboxylic acid or amino acid, secondary amine, solvent and catalyst, and reacting at 30° C. to 50° C. to prepare a β-acyloxy enamide derivative.

[0029] In some embodiments, the method specifically includes the following steps:

[0030] (1) In a 20 mL clean sealed tube, add 1.0 mmol of acyl chloride, 1.1 mmol of aluminum chloride, and 1.0 mL of dichloromethane (DCM) as a medium. Stir at 60°C for 30 minutes. Then add 1.8 mmol of vinylidene chloride and continue stirring for one hour.

[0031] After the reaction is completed, the crude product of trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating the liquids, drying with anhydrous Na2SO4 and concentrating.

[0032] The reaction equation is:

[0033]

[0034] In the formula, 1 represents an acyl chloride, 2 represents aluminum chloride, 3 represents vinylidene chloride, 4 represents α-trichloromethyl ketone; and R1 is an aromatic group.

[0035] (2) Add 1 mmol of α-trichloromethyl ketone, 3 mmol of carboxylic acid or amino acid, 1.5 mmol of secondary amine, and 2.5 mmol of cesium carbonate to a clean reaction tube, add an appropriate amount of acetone as solvent, and stir at 40 °C under air atmosphere for 1.5 hours or monitor the reaction by TLC until the reaction is completed;

[0036] After the reaction is completed, the reaction solution is extracted, separated, dried and concentrated, and then purified by silica gel column chromatography to obtain the target product β-acyloxy enamide derivative of the first step reaction.

[0037] The reaction equation is:

[0038]

[0039] In the formula, 4 represents α-trichloromethyl ketone, 5 represents carboxylic acid or amino acid, 6 represents secondary amine, 7 represents β-acyloxy enamide derivative; R1 is aryl, R2 is alkyl, aryl, alkenyl, etc., R3 is an aliphatic substituent group, and R4 is an aliphatic substituent group.

[0040] In the preparation method, the carboxylic acid or amino acid can be a fatty acid (such as sorbic acid), an aromatic acid, a heterocyclic acid, an olefinic acid, an α-amino acid or the like carboxylic acid.

[0041] In the preparation method, the secondary amine may be diethylamine, diisobutylamine, di-n-propylamine, or the like.

[0042] In the preparation method, the optimal molar ratio of α-trichloromethyl ketone, carboxylic acid and secondary amine is 1.0:3.0:1.5.

[0043] In the preparation method, acetone is used as the solvent, which can be replaced by a mixture of N,N-dimethylformamide and water or dimethyl sulfoxide. The amount of the solvent used is the conventional amount that can completely dissolve the solute, that is, the appropriate amount.

[0044] In this preparation method, the optimal reaction temperature is 40 °C.

[0045] In this method, the optimal reaction time is 1.5 hours.

[0046] The raw material α-trichloromethyl ketone is used in the present invention because it can be effectively purified by a convenient extraction method, thereby avoiding the use of complex separation methods such as column chromatography. These properties make it possible to save costs and improve efficiency in the organic synthesis process, thereby achieving a green and efficient synthesis of β-acyloxy enamide. By adding 1.0 mmol of acyl chloride, 1.1 mmol of aluminum chloride, and 1.0 mL of DCM as a medium in a 20 mL clean sealed tube, stirring at 60° C. for 30 minutes, then adding 1.8 mmol of vinylidene chloride, and continuing to stir for one hour. After quenching with a saturated NaHCO3 solution, extraction with ethyl acetate, separation, drying over anhydrous Na2SO4, and concentration, α-trichloromethyl ketone can be obtained.

[0047] Subsequently, the applicant explored and optimized the conditions for the direct synthesis of β-acyloxy enamides through the three-component reaction of α-trichloromethyl ketone, secondary amine and carboxylic acid. Taking the reaction of α-trichloromethyl, diethylamine and benzoic acid as a model, the applicant optimized different reaction parameters. First, cesium carbonate was fixed as the base, the equivalent of the acid was 3.0, and the equivalent of the secondary amine was 1.5. Under 40°C, different media (such as DMSO, DCE, DMF, EA, acetone, CH3CN, etc.) were used to react for 1.5 hours to obtain the final product with a yield of 51-77%. The highest yield came from the reaction with acetone as the medium. Subsequently, acetone was fixed as the medium, and the types of bases were changed to tetra-tert-butylammonium hydroxide, sodium tert-butoxide, sodium carbonate, sodium hydroxide, lithium hydroxide and cesium carbonate, and the target product could also be obtained with a yield of 30-40%, but the result was not better than cesium carbonate. Subsequently, by adjusting the equivalent of cesium carbonate, it was found that the yield was optimal at 2.5 moles of cesium carbonate, which was 64%. Finally, the reaction time, temperature, and solvent volume were optimized to obtain the optimal conditions; specifically, the feed ratio of α-trichloromethyl ketone, carboxylic acid or amino acid, and secondary amine was fixed at 1:3:1.5, 2 mL of acetone was used as the medium, 2.5 molar equivalents of cesium carbonate was used as the base, and the reaction was carried out for 1.5 hours. Different reaction temperatures (20 o C. 40 o C and 60 o C), and it was found that when the reaction temperature was 20 o C and 60 oC, the yields were 51% and 49%, respectively. o C, the yield was 77%, indicating that the reaction temperature was 40 o C is the optimal condition. Based on the experimental results of this part, the applicant selected α-trichloromethyl ketone, carboxylic acid or amino acid and secondary amine as feed ratios of 1:3:1.5, 2 mL acetone as medium, 2.5 molar equivalents of cesium carbonate as base, 40 o C reaction time of 1.5 h is the best reaction condition for synthesizing β-acyloxy enamide and / or polypeptide.

[0048] Another embodiment of the present invention provides the use of β-acyloxy enamide derivatives in the synthesis of amides and / or polypeptides, which comprises the following steps:

[0049] The β-acyloxy enamide derivative, the amine compound and the solvent are continuously stirred and reacted at a temperature of 0-80°C, and a TLC spot plate is used to monitor until the reaction is completed to obtain a reaction solution;

[0050] The reaction solution is separated and purified to obtain amide and / or polypeptide.

[0051] In some embodiments, the method specifically includes the following steps:

[0052] (1) Add 0.2 mmol of β-acyloxy enamide derivative, 0.24 mmol of amine compound and an appropriate amount of ethyl acetate (EA) as solvent to a clean reaction tube, and react at a temperature of 0 to 80 °C with constant stirring;

[0053] (2) The reaction in the previous step is monitored by TLC spot plate. After the reaction in the previous step is completed, the solvent is concentrated and separated and purified by column chromatography to directly obtain the amide and / or peptide.

[0054] Among them, the chemical reaction formula of step (1) is:

[0055]

[0056] In the formula, 7 represents a β-acyloxy enamide derivative, 8 represents an amine compound, 9 represents an amide and / or a polypeptide, and 10 represents an amide by-product; R1 can be an aryl group, R2 can be an alkyl group, an aryl group, an alkenyl group, etc., R3 is an aliphatic substituent group, R4 is an aliphatic substituent group, R5 is an aliphatic substituent group, and R6 is an aliphatic substituent group.

[0057] In the application method, the amine compound is a secondary amine.

[0058] In the application method, the optimal molar ratio of the β-acyloxy enamide derivative to the amine compound is 0.2:0.24.

[0059] In the application method, ethyl acetate is used as a solvent, and the amount of the solvent used is a conventional amount that can completely dissolve the solute, that is, an appropriate amount.

[0060] In this application method, the optimal reaction temperature is 30°C.

[0061] The β-acyloxy enamide derivative synthesized by the above method is an activated carboxylic acid. When it is placed in a conventional organic solvent (such as ethyl acetate) and stirred, an amide bond construction reaction can be achieved at room temperature or a temperature close to that, thereby efficiently obtaining amide products. When an amino acid is used as a substrate when synthesizing a β-acyloxy enamide derivative, the corresponding β-acyloxy enamide derivative and an amino acid ester undergo an amide bond construction reaction to directly obtain the target product, a polypeptide. The polypeptide product was subjected to chiral liquid chromatography analysis, and the analysis results showed that the obtained peptide products were all optically pure samples, and no racemization phenomenon occurred during the reaction process, which fully confirmed that the method of the present invention has a great application prospect in the field of amide synthesis and peptide condensation.

[0062] The present invention is further described in detail below with specific examples, but the present invention is not limited to the following specific examples.

[0063] The first part is a specific example of a mild and efficient preparation method of β-acyloxy enamide derivatives, see Examples 1 to 21 for details.

[0064] Example 1

[0065] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as the medium. o C for 30 minutes, then add 1.8 mmol of vinylidene chloride and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating the liquids, drying with anhydrous Na2SO4 and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), benzoic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1.5 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is removed by filtration. The solvent in the resulting solution is removed under reduced pressure, and the resulting residue is subjected to column chromatography to obtain a pure product, a yellow solid, with a yield of 77%.

[0066] The following is the structural formula and NMR experimental data of the product:

[0067]

[0068] 1 H NMR (400 MHz, CDCl3) δ 8.26 – 8.12 (m, 2H), 7.65 – 7.55 (m, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.41 – 7.35 (m, 3H), 6.50 (s, 1H), 3.42 (dq, J =40.1, 7.1 Hz, 4H), 1.23 (t, J = 7.2 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H).

[0069] 13 C NMR (100 MHz, CDCl3) δ 164.05, 152.63, 134.23, 133.58, 130.36,129.89, 129.30, 128.74, 128.60, 125.53, 109.15, 42.56, 39.64, 14.45, 12.93.

[0070] Example 2

[0071] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), 4-methylbenzoic acid (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) were added to a clean 25 mL reaction tube, and an appropriate amount of acetone was added as a solvent. The reaction was carried out at 40 degrees Celsius for 1.5 hours, and the TLC spot plate was monitored. After the reaction was completed, it was cooled to room temperature, a small amount of water was added, and the resulting mixture was extracted with ethyl acetate. The organic phase was collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid was filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain the pure product as a yellow solid in a yield of 55%.

[0072] The following is the structural formula and NMR experimental data of the product:

[0073]

[0074] 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J = 7.8 Hz, 2H), 7.57 (d, J = 3.4Hz, 2H), 7.36 (s, 3H), 7.27 (d, J = 7.9 Hz, 2H), 6.48 (s, 1H), 3.46 (d, J =7.2 Hz, 2H), 3.36 (t, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H), 1.03 (t, J = 6.9 Hz, 3H).

[0075] 13 C NMR (100 MHz, CDCl3) δ 164.12, 164.08, 152.52, 144.40, 134.32,130.39, 129.81, 129.31, 128.71, 126.57, 125.50, 109.21, 42.55, 39.57, 21.73,14.44, 12.93.

[0076] Example 3

[0077] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), m-fluorobenzoic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is removed by filtration. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a white solid in a yield of 67%.

[0078] The following is the structural formula and NMR experimental data of the product:

[0079]

[0080] 11H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.7 Hz, 1H), 7.86 (d, J = 9.2Hz, 1H), 7.58 (d, J = 3.9 Hz, 2H), 7.47 (s, 1H), 7.40 (d, J = 2.7 Hz, 3H),7.30 (td, J = 8.8, 2.7 Hz, 1H), 6.51 (s, 1H), 3.46 (q, J = 7.1 Hz, 2H), 3.37(q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H).

[0081] 13 13C NMR (100 MHz, CDCl3) δ 164.05, 162.93, 162.73 (d, J = 244.5 Hz),152.83, 134.02, 131.49 (d, J = 7.7 Hz), 130.29 (d, J = 8.0 Hz), 130.05,128.79, 126.10 (d, J = 3.2 Hz), 125.53, 120.65 (d, J = 21.3 Hz), 117.17 (d, J= 23.3 Hz), 108.84, 42.58, 39.78, 14.47, 12.95.

[0082] Example 4

[0083] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), 2-iodo-5-methylbenzoic acid (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain the pure product as a white solid in a yield of 53%.

[0084] The following is the structural formula and NMR experimental data of the product:

[0085]

[0086] 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 2.3 Hz, 1H), 7.88 (d, J = 8.1Hz, 1H), 7.60 (d, J = 3.6 Hz, 2H), 7.39 (s, 3H), 7.01 (dd, J = 8.1, 2.3 Hz,1H), 6.50 (s, 1H), 3.44 (dq, J = 27.3, 7.1 Hz, 4H), 2.36 (s, 3H), 1.24 (t, J= 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H).

[0087] 13 C NMR (100 MHz, CDCl3) δ 163.97, 163.41, 152.72, 141.20, 138.39,134.32, 133.96, 133.40, 132.82, 129.96, 128.73, 125.70, 109.15, 90.74, 42.67,39.78, 20.92, 14.46, 13.06.

[0088] Example 5

[0089] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), cyclohexanecarboxylic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1 hour, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 85%.

[0090] The following is the structural formula and NMR experimental data of the product:

[0091]

[0092] 1 H NMR (400 MHz, CDCl3) δ 7.54 – 7.45 (m, 2H), 7.41 – 7.33 (m, 3H), 6.37 (s, 1H), 3.41 (dd, J = 7.1, 3.2 Hz, 4H), 2.61 (t, J = 11.4 Hz, 1H), 2.10(d, J = 11.5 Hz, 2H), 1.80 (d, J = 13.2 Hz, 2H), 1.67 (d, J = 11.5 Hz, 1H), 1.55 (t, J = 10.4 Hz, 2H), 1.38 – 1.24 (m, 3H), 1.20 (t, J = 7.2 Hz, 3H),1.14 (t, J = 7.1 Hz, 3H).

[0093] 13C NMR (100 MHz, CDCl3) δ 173.09, 164.17, 152.54, 134.50, 129.71,128.63, 125.41, 108.79, 43.10, 42.52, 39.73, 28.80, 28.40, 25.73, 25.38,25.14, 14.31, 13.03.

[0094] Example 6

[0095] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), sorbic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1 hour, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 59%.

[0096] The following is the structural formula and NMR experimental data of the product:

[0097]

[0098] 1 H NMR (400 MHz, CDCl3) δ 7.56 – 7.49 (m, 2H), 7.48 – 7.40 (m, 1H), 7.39 – 7.35 (m, 3H), 6.40 (s, 1H), 6.29 – 6.13 (m, 2H), 5.98 (d, J = 15.4 Hz, 1H), 3.42 (dt, J = 14.4, 7.2 Hz, 4H), 1.87 (d, J = 6.0 Hz, 3H), 1.21 (t, J =7.2 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H).

[0099] 13C NMR (100 MHz, CDCl3) δ 164.37, 164.17, 152.44, 147.30, 140.63,134.38, 130.33, 129.88, 128.63, 125.50, 117.67, 108.86, 42.51, 39.61, 18.69,14.38, 12.98.

[0100] Example 7

[0101] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), veratric acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1 hour, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a white solid with a yield of 70%.

[0102] The following is the structural formula and NMR experimental data of the product:

[0103]

[0104] 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.4 Hz, 1H), 7.65 (d, J = 2.0Hz, 1H), 7.60 – 7.54 (m, 2H), 7.38 (q, J = 3.4 Hz, 3H), 6.94 (d, J = 8.5 Hz,1H), 6.48 (s, 1H), 3.94 (d, J = 8.4 Hz, 6H), 3.48 (q, J = 7.1 Hz, 2H), 3.38(q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.3 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H).

[0105] 13 C NMR (100 MHz, CDCl3) δ 164.15, 163.81, 153.65, 152.63, 148.83,134.36, 129.81, 128.70, 125.52, 124.67, 121.70, 112.61, 110.52, 109.14,56.10, 56.06, 42.55, 39.60, 14.43, 12.94.

[0106] Example 8

[0107] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), ibuprofen (3 mmol), cesium carbonate (2.5 mmol), and diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2.5 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is removed by filtration. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a white solid in a yield of 64%.

[0108] The following is the structural formula and NMR experimental data of the product:

[0109]

[0110] 1 H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 7.8 Hz, 3H), 7.23 – 7.09 (m,7H), 6.35 (s, 1H), 3.45 – 3.33 (m, 4H), 2.48 (d, J = 7.1 Hz, 2H), 1.86 (dq, J = 13.5, 6.8 Hz, 1H), 1.59 (d, J = 7.2 Hz, 3H), 1.17 (dd, J = 15.6, 8.4 Hz, 6H), 0.92 (d, J = 6.6 Hz, 6H).

[0111] 13 C NMR (100 MHz, CDCl3) δ 171.75, 164.11, 152.47, 140.73, 137.23,134.10, 129.67, 129.40, 128.46, 127.64, 125.27, 108.53, 45.18, 45.06, 42.52,39.78, 30.24, 22.36, 17.89, 14.36, 13.04.

[0112] Example 9

[0113] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), flurbiprofen (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2.5 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the obtained solution was removed under reduced pressure, and the obtained residue was subjected to column chromatography to obtain a pure product as a light yellow liquid with a yield of 70%.

[0114] The following is the structural formula and NMR experimental data of the product:

[0115]

[0116] 11H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.1 Hz, 2H), 7.44 (q, J = 7.5Hz, 3H), 7.38 (d, J = 7.2 Hz, 1H), 7.27 (d, J = 5.4 Hz, 6H), 7.21 (d, J =11.5 Hz, 1H), 6.37 (s, 1H), 3.40 (s, 4H), 1.65 (d, J = 7.2 Hz, 3H), 1.20 (tt,J = 25.1, 7.1 Hz, 7H).

[0117] 13 13C NMR (100 MHz, CDCl3) δ 171.16, 163.97, 159.77 (d, J = 248.7 Hz),152.73, 141.38 (d, J = 7.7 Hz), 135.58, 134.13, 130.85 (d, J = 4.0 Hz),130.35, 129.86, 128.97 (d, J = 2.9 Hz), 128.74, 128.62, 128.49, 128.07,127.93, 127.70, 125.54, 125.38, 124.07 (d, J = 3.5 Hz), 115.70 (d, J = 23.8Hz), 108.59, 45.10, 42.53, 39.86, 17.99, 14.38, 13.04.

[0118] Example 10

[0119] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), furoic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2.5 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 40%.

[0120] The following is the structural formula and NMR experimental data of the product:

[0121]

[0122] 1 H NMR (400 MHz, CDCl3) δ 7.66 – 7.54 (m, 3H), 7.39 (d, J = 2.5 Hz,4H), 6.56 (d, J = 1.7 Hz, 1H), 6.49 (s, 1H), 3.49 – 3.37 (m, 4H), 1.23 (t, J = 7.2 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H).

[0123] 13 C NMR (100 MHz, CDCl3) δ 163.83, 155.58, 151.93, 147.21, 143.81,134.01, 129.99, 128.73, 125.58, 119.72, 112.22, 109.13, 42.58, 39.74, 14.41,12.90.

[0124] Embodiment 11

[0125] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), Boc-L-tryptophan (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dimethyl sulfoxide is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 51%.

[0126] The following is the structural formula and NMR experimental data of the product:

[0127]

[0128] 1 H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.47– 7.41 (m, 2H), 7.32 (dd, J = 16.4, 8.1 Hz, 4H), 7.13 (dt, J = 26.0, 7.0 Hz, 3H), 6.39 (s, 1H), 5.31 (d, J = 7.8 Hz, 1H), 4.85 (d, J = 6.9 Hz, 1H), 3.54(dd, J = 15.2, 5.4 Hz, 1H), 3.41 (q, J = 7.1 Hz, 4H), 3.29 (dd, J = 15.2, 7.7Hz, 1H), 1.37 (s, 9H), 1.26 (d, J = 7.1 Hz, 3H), 1.14 (t, J = 7.1 Hz, 3H).

[0129] 13C NMR (100 MHz, CDCl3) δ 169.94, 164.09, 155.53, 152.98, 136.24,133.60, 129.94, 128.65, 127.83, 125.70, 123.45, 121.89, 119.41, 118.81,111.22, 110.34, 108.62, 79.76, 54.66, 42.65, 39.95, 28.30, 27.32, 14.37,13.08.

[0130] Example 12

[0131] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), Fmoc-L-aspartic acid-beta-tert-butyl ester (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) were added to a clean 25 mL reaction tube, and an appropriate amount of dimethyl sulfoxide was added as a solvent. The reaction was carried out at 40 degrees Celsius for 6 hours, and the TLC spot plate was monitored. After the reaction was completed, it was cooled to room temperature, a small amount of water was added, and the resulting mixture was extracted with ethyl acetate. The organic phase was collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid was filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow solid in a yield of 42%.

[0132] The following is the structural formula and NMR experimental data of the product:

[0133]

[0134] 11H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 7.6 Hz, 2H), 7.64 – 7.54 (m, 4H), 7.37 (t, J = 4.9 Hz, 5H), 7.28 (dd, J = 7.2, 2.8 Hz, 2H), 6.41 (s, 1H), 6.29 (d, J = 8.2 Hz, 1H), 5.05 – 4.94 (m, 1H), 4.39 (td, J = 14.4, 12.5, 7.6 Hz, 2H), 4.24 (t, J = 7.4 Hz, 1H), 3.46 – 3.36 (m, 4H), 3.00 (d, J = 5.7 Hz, 2H), 1.45 (s, 9H), 1.18 (dt, J = 31.2, 7.2 Hz, 6H).

[0135] 13 13C NMR (100 MHz, CDCl3) δ 170.07, 168.64, 163.76, 156.06, 154.13, 143.85, 141.28, 133.67, 130.25, 128.73, 127.66, 127.06, 125.80, 125.23, 119.92, 107.06, 81.58, 67.28, 51.22, 47.15, 42.64, 40.29, 37.57, 28.06, 14.49, 13.06.

[0136] Example 13

[0137] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating the liquids, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), thiophenecarboxylic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a light yellow solid with a yield of 70%.

[0138] The following is the structural formula and NMR experimental data of the product:

[0139]

[0140] 1 H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 3.8 Hz, 1H), 7.67 – 7.52 (m,3H), 7.43 – 7.32 (m, 3H), 7.20 – 7.08 (m, 1H), 6.48 (s, 1H), 3.42 (dq, J =29.5, 7.1 Hz, 4H), 1.23 (t, J = 7.1 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H).

[0141] 13 C NMR (100 MHz, CDCl3) δ 163.96, 159.28, 152.04, 134.91, 134.10,133.62, 132.52, 129.93, 128.74, 128.06, 125.55, 109.34, 42.57, 39.67, 14.44,12.92.

[0142] Embodiment 14

[0143] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), Boc-L-proline (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1 hour, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 49%.

[0144] The following is the structural formula and NMR experimental data of the product:

[0145]

[0146] 1 H NMR (400 MHz, CDCl3) δ 7.64 (dd, J = 6.7, 3.0 Hz, 1H), 7.57 – 7.51(m, 1H), 7.37 (d, J = 6.1 Hz, 3H), 6.40 (d, J = 2.0 Hz, 1H), 4.53 (td, J =9.0, 3.0 Hz, 1H), 3.63 – 3.53 (m, 1H), 3.50 – 3.36 (m, 5H), 2.62 – 2.41 (m,1H), 2.40 – 2.05 (m, 2H), 1.94 – 1.87 (m, 1H), 1.44 (d, J = 24.2 Hz, 9H),1.25 – 1.19 (m, 3H), 1.14 (t, J = 7.1 Hz, 3H).

[0147] 13C NMR (150 MHz, CDCl3) δ 170.17, 169.51, 164.17, 163.94, 154.50,153.93, 152.40, 152.08, 134.03, 133.69, 129.90, 129.73, 128.58, 125.84,125.58, 109.41, 108.97, 80.12, 79.74, 59.10, 59.08, 46.70, 46.48, 42.56,39.70, 39.68, 29.95, 29.19, 28.46, 28.38, 24.41, 23.37, 14.22, 13.10.

[0148] Embodiment 15

[0149] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), benzoic acid (3 mmol), cesium carbonate (2.5 mmol), diisobutylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 0.5 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is removed by filtration. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 50%.

[0150] The following is the structural formula and NMR experimental data of the product:

[0151]

[0152] 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 7.0 Hz, 2H), 7.62 – 7.52 (m,3H), 7.47 (t, J = 7.7 Hz, 2H), 7.40 – 7.34 (m, 3H), 6.52 (s, 1H), 3.25 (d, J = 7.5 Hz, 2H), 3.20 (d, J = 7.6 Hz, 2H), 1.95 (dq, J = 20.7, 6.9 Hz, 2H), 0.96 (d, J = 6.7 Hz, 6H), 0.78 (d, J = 6.7 Hz, 6H).

[0153] 13 C NMR (100 MHz, CDCl3) δ 165.19, 164.04, 151.90, 134.28, 133.56,130.39, 129.77, 129.25, 128.75, 128.53, 125.41, 110.28, 56.06, 52.37, 27.76,26.43, 20.17, 20.08.

[0154] Example 16

[0155] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), pyrrole-2-carboxylic acid (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1 hour, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow solid in a yield of 36%.

[0156] The following is the structural formula and NMR experimental data of the product:

[0157]

[0158] 1 H NMR (400 MHz, CDCl3) δ 9.93 (s, 1H), 7.58 – 7.51 (m, 2H), 7.36 (dd,J = 5.1, 2.0 Hz, 2H), 7.15 – 7.08 (m, 1H), 6.93 (q, J = 2.4 Hz, 1H), 6.42 (s,1H), 6.27 (dd, J = 4.2, 2.3 Hz, 1H), 3.43 (q, J = 7.2 Hz, 2H), 3.37 (q, J =7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H), 1.04 (t, J = 7.1 Hz, 3H).

[0159] 13 C NMR (100 MHz, CDCl3) δ 164.37, 158.03, 152.04, 134.33, 129.79,128.66, 125.55, 124.36, 121.49, 117.31, 110.68, 109.30, 42.60, 39.62, 14.36,12.83.

[0160] Embodiment 17

[0161] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), 2-bromobenzoic acid (3 mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 56%.

[0162] The following is the structural formula and NMR experimental data of the product:

[0163]

[0164] 1 H NMR (400 MHz, CDCl3) δ 8.19 (dd, J = 7.7, 1.9 Hz, 1H), 7.70 – 7.59(m, 3H), 7.38 (tt, J = 10.6, 4.7 Hz, 5H), 6.51 (s, 1H), 3.44 (dt, J = 22.4,7.1 Hz, 4H), 1.23 (t, J = 7.0 Hz, 3H), 1.09 (t, J = 7.1 Hz, 3H).

[0165] 13 C NMR (100 MHz, CDCl3) δ 163.89, 163.05, 152.84, 134.23, 133.92,133.04, 132.37, 131.23, 130.01, 128.75, 127.46, 125.69, 122.02, 109.05,42.64, 39.83, 14.45, 13.04.

[0166] Embodiment 18

[0167] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), benzoic acid (3 mmol), cesium carbonate (2.5 mmol), and di-n-propylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of acetone is added as a solvent. The reaction is carried out at 40 degrees Celsius for 2.5 hours, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 19%.

[0168] The following is the structural formula and NMR experimental data of the product:

[0169]

[0170] 1H NMR (400 MHz, CDCl3) δ 8.23 ​​– 8.13 (m, 2H), 7.63 – 7.54 (m, 3H), 7.48 (t, J = 7.6 Hz, 2H), 7.38 (s, 3H), 6.50 (s, 1H), 3.37 (t, J = 7.6 Hz,2H), 3.28 (t, J = 7.6 Hz, 2H), 1.65 (q, J = 7.5 Hz, 2H), 1.48 (h, J = 7.5 Hz,2H), 0.96 (t, J = 7.4 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H).

[0171] 13 C NMR (100 MHz, CDCl3) δ 164.53, 164.02, 152.37, 134.30, 133.54,130.37, 129.82, 129.31, 128.74, 128.56, 125.50, 109.51, 50.07, 46.91, 22.27, 20.74, 11.33, 11.30.

[0172] Embodiment 19

[0173] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), Boc-L-serine (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dimethyl sulfoxide is added as a solvent. The reaction is carried out at 40 degrees Celsius for 1 hour, and the TLC spot plate is monitored. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the obtained solution was removed under reduced pressure, and the obtained residue was subjected to column chromatography to obtain a pure product as a light yellow liquid with a yield of 49%.

[0174] The following is the structural formula and NMR experimental data of the product:

[0175]

[0176] 1 H NMR (400 MHz, CDCl3) δ 7.61 – 7.53 (m, 2H), 7.44 – 7.36 (m, 3H), 6.44 (s, 1H), 5.71 (d, J = 8.8 Hz, 1H), 4.66 (s, 1H), 4.57 – 4.43 (m, 1H), 4.41 – 4.33 (m, 1H), 3.82 (dd, J = 12.4, 4.1 Hz, 1H), 3.41 (dq, J = 14.6, 7.2Hz, 4H), 1.46 (s, 9H), 1.25 (t, J = 7.1 Hz, 3H), 1.14 (t, J = 7.0 Hz, 3H).

[0177] 13 C NMR (100 MHz, CDCl3) δ 169.04, 164.27, 155.72, 154.61, 133.46,130.49, 128.81, 125.82, 106.39, 79.91, 63.28, 56.42, 42.82, 40.59, 28.33,14.33, 13.00.

[0178] Embodiment 20

[0179] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating the liquids, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), 2,3,5-triiodobenzoic acid (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) were added to a clean 25 mL reaction tube, and an appropriate amount of acetone was added as a solvent. The reaction was carried out at 40 degrees Celsius for 7 hours, and the reaction was monitored by TLC spot plate. After the reaction was completed, it was cooled to room temperature, a small amount of water was added, and the resulting mixture was extracted with ethyl acetate. The organic phase was collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid was filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a light yellow solid in a yield of 51%.

[0180] The following are the structural formula, NMR experimental data and mass spectrometry experimental data of the product:

[0181]

[0182] 1 1H NMR (400 MHz, CDCl3) δ 8.33 (dd, J = 23.6, 2.1 Hz, 2H), 7.63 (dd, J = 6.7, 3.1 Hz, 2H), 7.42 (d, J = 2.8 Hz, 3H), 6.50 (s, 1H), 3.44 (p, J = 6.8 Hz, 4H), 1.20 (dt, J = 39.3, 7.1 Hz, 6H).

[0183] 13 13C NMR (100 MHz, CDCl3) δ 163.66, 162.69, 153.05, 149.32, 140.15, 138.43, 133.53, 130.24, 128.78, 125.84, 113.26, 108.77, 107.02, 94.05, 42.65, 40.07, 14.49, 13.17.

[0184] HRMS (ESI-TOF) m / z: [M + H] + Calcd for C 20 H 18 I3NO3 701.8494; Found 701.8481.

[0185] Example 21

[0186] In a 20 mL clean sealed tube, add 1.0 mmol benzoyl chloride, 1.1 mmol aluminum chloride, and 1.0 mL DCM as a medium, stir at 60°C for 30 minutes, then add 1.8 mmol vinylidene chloride, and continue stirring for one hour. After the reaction is completed, α-trichloromethyl ketone can be obtained by quenching with saturated NaHCO3 solution, extracting with ethyl acetate, separating, drying with anhydrous Na2SO4, and concentrating. Subsequently, α-trichloromethyl ketone (1 mmol), Cbz-L-alanine (3mmol), cesium carbonate (2.5 mmol), diethylamine (1.5 mmol) are added to a clean 25 mL reaction tube, and an appropriate amount of dimethyl sulfoxide is added as a solvent. The reaction is carried out at 40 degrees Celsius for 3 hours, and the reaction is monitored by TLC spot plate. After the reaction is completed, it is cooled to room temperature, a small amount of water is added, and the resulting mixture is extracted with ethyl acetate. The organic phase is collected and washed three times with a small amount of water. After drying with anhydrous Na2SO4, the solid is filtered out. The solvent in the resulting solution was removed under reduced pressure, and the resulting residue was subjected to column chromatography to obtain a pure product as a yellow liquid with a yield of 61%.

[0187] The following is the structural formula and NMR experimental data of the product:

[0188]

[0189] 1 H NMR (400 MHz, CDCl3) δ 7.55 – 7.26 (m, 10H), 6.39 (s, 1H), 5.85 (d,J = 7.8 Hz, 1H), 5.18 – 5.03 (m, 2H), 4.68 (q, J = 7.3 Hz, 1H), 3.38 (q, J =7.2 Hz, 4H), 1.57 (d, J = 7.1 Hz, 3H), 1.15 (dt, J = 33.5, 7.1 Hz, 6H).

[0190] 13 C NMR (100 MHz, CDCl3) δ 170.31, 163.78, 155.96, 153.45, 136.46,133.69, 130.15, 128.78, 128.47, 128.04, 128.00, 125.59, 107.75, 66.82, 50.00, 42.58, 40.05, 17.87, 14.42, 13.06.

[0191] The second part is a specific implementation method of the application of β-acyloxy enamide derivatives in polypeptide synthesis, see Examples 22-27 for details.

[0192] Embodiment 22

[0193] In a clean 25 mL reaction tube, add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl(tert-butyloxycarbonyl)-L-tryptophanate (0.2 mmol) and L-valine tert-butyl ester (0.24 mmol) prepared in Example 11, add an appropriate amount of ethyl acetate as solvent, react at 30 degrees Celsius for 18 hours, and monitor by TLC spot plate. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product as a yellow liquid with a yield of 65%.

[0194] The following is the structural formula and NMR experimental data of the product:

[0195]

[0196] 1 H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.34(d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.11 (t, J = 7.4 Hz, 1H), 1.47 (s, 1H), 1.42 (s, 18H), 0.81 (d, J = 6.8 Hz, 6H).

[0197] 13 C NMR (100 MHz, CDCl3) δ 171.55, 170.50, 155.54, 136.28, 127.56,123.23, 122.17, 119.64, 118.86, 111.18, 110.60, 81.87, 80.10, 57.66, 55.25,31.36, 28.28, 28.01, 18.62, 17.75.

[0198] Embodiment 23

[0199] In a clean 25 mL reaction tube, add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl(tert-butyloxycarbonyl)-L-tryptophanate (0.2 mmol) prepared in Example 11 and tert-butyl L-aspartate (0.24 mmol), add an appropriate amount of ethyl acetate as solvent, react at 30 degrees Celsius for 15 hours, and monitor by TLC spot plate. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product as a light yellow solid with a yield of 80%.

[0200] The following is the structural formula and NMR experimental data of the product:

[0201]

[0202] 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.38– 7.28 (m, 2H), 7.17 – 7.03 (m, 3H), 5.95 (d, J = 22.9 Hz, 2H), 5.33 (d, J =40.2 Hz, 1H), 4.63 – 4.40 (m, 2H), 3.34 – 3.15 (m, 2H), 2.64 (dt, J = 16.4,8.1 Hz, 2H), 1.40 (d, J = 16.8 Hz, 18H).

[0203] 13 C NMR (100 MHz, CDCl3) δ 172.65, 172.19, 169.76, 155.63, 136.35,127.69, 123.65, 121.89, 119.30, 118.84, 111.42, 109.85, 82.49, 80.18, 53.43,49.82, 37.27, 28.26, 28.07, 27.88.

[0204] Embodiment 24

[0205] In a clean 25 mL reaction tube, add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl (tert-butoxycarbonyl)-L-serine ester (0.2 mmol) prepared in Example 19 and L-tyrosine tert-butyl ester (0.24 mmol), add an appropriate amount of ethyl acetate as solvent, react at 30 degrees Celsius for 15 hours, and monitor by TLC spot plate. After the reaction is completed, the organic layer is concentrated and column chromatographed to obtain a pure product as a yellow liquid with a yield of 80%.

[0206] The following is the structural formula and NMR experimental data of the product:

[0207]

[0208] 1 H NMR (400 MHz, CDCl3) δ 7.24 – 7.12 (m, 1H), 7.08 (s, 1H), 6.98 (d,J = 8.0 Hz, 2H), 6.72 (d, J = 8.1 Hz, 2H), 5.65 (s, 1H), 4.66 (s, 1H), 4.03(d, J = 106.0 Hz, 2H), 3.63 – 3.57 (m, 1H), 3.00 (ddd, J = 48.3, 14.1, 6.0Hz, 2H), 2.26 (s, 1H), 1.44 (d, J = 2.5 Hz, 18H).

[0209] 13 C NMR (100 MHz, CDCl3) δ 170.96, 170.69, 155.99, 155.40, 130.54,127.19, 115.51, 82.79, 80.64, 62.77, 55.36, 54.11, 36.84, 28.28, 27.98.

[0210] Embodiment 25

[0211] In a clean 25 mL reaction tube, add (Z)-3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl((benzyloxy)carbonyl)-L-alaninate (0.2 mmol) and L-phenylalanine tert-butyl ester (0.24 mmol) prepared in Example 21, add an appropriate amount of ethyl acetate as solvent, react at 30 degrees Celsius for 12 hours, and monitor by TLC. After the reaction, the organic layer is concentrated and column chromatographed to obtain a pure product as a yellow liquid with a yield of 90%.

[0212] The following is the structural formula and NMR experimental data of the product:

[0213]

[0214] 1H NMR (400 MHz, CDCl3) δ 7.34 (s, 5H), 7.26 – 7.18 (m, 3H), 7.13 (d,J = 7.1 Hz, 2H), 6.58 (d, J = 7.6 Hz, 1H), 5.42 (d, J = 7.6 Hz, 1H), 5.10 (t,J = 9.5 Hz, 2H), 4.77 – 4.63 (m, 1H), 4.25 (s, 1H), 3.07 (d, J = 3.1 Hz, 2H), 1.40 (s, 9H), 1.33 (d, J = 6.9 Hz, 3H).

[0215] 13 C NMR (100 MHz, CDCl3) δ 171.72, 170.29, 155.86, 136.27, 136.05,129.52, 128.54, 128.37, 128.17, 128.05, 126.97, 82.44, 66.99, 53.63, 50.47,37.96, 27.95, 18.60.

[0216] Embodiment 26

[0217] In a clean 25 mL reaction tube, (Z)-4-(tert-butyl) 1-(3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartate (0.2 mmol) and L-valine tert-butyl ester (0.24 mmol) prepared in Example 12 were added, and an appropriate amount of ethyl acetate was added as a solvent. The reaction was carried out at 30 degrees Celsius for 14 hours and monitored by TLC spot plate. After the reaction was completed, the organic layer was concentrated and column chromatographed to obtain a pure product as a colorless liquid with a yield of 79%.

[0218] The following is the structural formula and NMR experimental data of the product:

[0219]

[0220] 1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.4Hz, 2H), 7.40 (t, J = 7.4 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.06 (d, J = 8.4Hz, 1H), 4.58 (s, 1H), 4.47 – 4.31 (m, 3H), 4.24 (t, J = 7.1 Hz, 1H), 2.93 (dd, J = 17.3, 4.2 Hz, 1H), 2.64 (dd, J = 17.3, 7.0 Hz, 1H), 2.17 (tt, J =11.5, 5.8 Hz, 1H), 2.05 (s, 1H), 1.45 (d, J = 2.9 Hz, 18H), 0.92 (dd, J =11.7, 6.9 Hz, 6H).

[0221] 13 C NMR (100 MHz, CDCl3) δ 171.41, 171.33, 170.37, 155.98, 143.74,141.31, 127.74, 127.10, 125.09, 120.00, 81.90, 81.87, 67.33, 57.85, 51.05,47.15, 37.66, 31.18, 28.05, 28.02, 18.94, 17.47.

[0222] Embodiment 27

[0223] In a clean 25 mL reaction tube, O-tert-butyl-L-serine tert-butyl ester hydrochloride (0.24 mmol), sodium bicarbonate (0.24 mmol), and an appropriate amount of ethyl acetate as a solvent were added, and the mixture was reacted at 30 degrees Celsius for 0.5 hours. Then, (Z)-4-(tert-butyl) 1-(3-(diethylamino)-3-oxo-1-phenylprop-1-en-1-yl)(((9H-fluoren-9-yl)methoxy)carbonyl)-L-aspartic acid ester (0.2 mmol) prepared in Example 12 was added, and the mixture was reacted at 30 degrees Celsius for 14 hours, and monitored by TLC spot plate. After the reaction, the organic layer was concentrated and column chromatographed to obtain a pure product as a colorless liquid with a yield of 75%.

[0224] The following is the structural formula and NMR experimental data of the product:

[0225]

[0226] 1 H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 7.6Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (t, J = 7.5 Hz, 3H), 6.04 (s, 1H), 4.64 (s, 1H), 4.53 (d, J = 8.3 Hz, 1H), 4.38 (d, J = 7.3 Hz, 2H), 4.23 (s,1H), 3.79 (dd, J = 8.8, 2.9 Hz, 1H), 3.52 (dd, J = 8.8, 3.1 Hz, 1H), 2.89 (d,J = 12.6 Hz, 1H), 2.69 (d, J = 10.1 Hz, 1H), 1.45 (d, J = 4.0 Hz, 18H), 1.14 (s, 9H).

[0227] 13 C NMR (100 MHz, CDCl3) δ 171.03, 170.36, 168.86, 155.84, 143.80,141.30, 127.72, 127.10, 125.13, 119.98, 81.74, 77.28, 73.13, 67.29, 61.88,53.53, 50.89, 47.16, 38.02, 28.08, 28.01, 27.32.

[0228] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.

Claims

1. A method for preparing a β-acyloxy enamide derivative, characterized in that: The following steps are involved: S1, mixing acyl chloride, aluminum chloride and solvent at 50°C to 70°C, and adding vinylidene chloride to mix, and reacting to obtain α-trichloromethyl ketone; S2, mixing the α-trichloromethyl ketone with a carboxylic acid or an amino acid, a secondary amine, a solvent and a catalyst to prepare a β-acyloxy enamide derivative; Among them, the reaction equation of S2 is as follows: R1 is an aryl group, R2 is an alkyl group, an aryl group or an alkenyl group, R3 is an aliphatic substituent group, and R4 is an aliphatic substituent group.

2. The preparation method according to claim 1, characterized in that: In S1, the molar ratio of the acyl chloride, aluminum chloride and vinylidene chloride is 1:0.5-1.5:1-3.

3. The preparation method according to claim 1, characterized in that: In S1, the mixing time of the acyl chloride, aluminum chloride and solvent is 20 min to 40 min, and the mixing time after the vinylidene chloride is continuously added is 40 to 80 min; In S2, the reaction was monitored by TLC until the reaction was completed.

4. The preparation method according to claim 1, characterized in that: In S2, the secondary amine is one or more of diethylamine, diisobutylamine and di-n-propylamine.

5. The preparation method according to claim 1, characterized in that: In S2, the carboxylic acid or amino acid is one or more of benzoic acid, 4-methylbenzoic acid, m-fluorobenzoic acid, 2-iodo-5-methylbenzoic acid, cyclohexanecarboxylic acid, sorbic acid, veratric acid, ibuprofen, flurbiprofen, furoic acid, Boc-L-tryptophan, Fmoc-L-aspartic acid-beta-tert-butyl ester, thiophenecarboxylic acid, Boc-L-proline, pyrrole-2-carboxylic acid, 2-bromobenzoic acid, Boc-L-serine, 2,3,5-triiodobenzoic acid and Cbz-L-alanine.

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